Promoting remyelination: utilizing a viral model of demyelination to assess cell-based therapies

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS. While a broad range of therapeutics effectively reduce the incidence of focal white matter inflammation and plaque formation for patients with relapse-remitting forms of MS, a challenge within the field is to develop therapies that allow for axonal protection and remyelination. In the last decade, growing interest has focused on utilizing neural precursor cells (NPCs) to promote remyelination. To understand how NPCs function in chronic demyelinating environments, several excellent pre-clinical mouse models have been developed. One well accepted model is infection of susceptible mice with neurotropic variants of mouse hepatitis virus (MHV) that undergo chronic demyelination exhibiting clinical and histopathologic similarities to MS patients. Combined with the possibility that an environmental agent such as a virus could trigger MS, the MHV model of demyelination presents a relevant mouse model to assess the therapeutic potential of NPCs transplanted into an environment in which inflammatory-mediated demyelination is established.

Keywords::

• demyelination
• multiple sclerosis
• neural precursor cells
• neural progenitor cells
• remyelination
• virus

Financial & competing interests disclosure

This work was supported by National Institutes of Health (NIH) grants R01 NS041249 and R01 NS074987 (TEL) as well as National Multiple Sclerosis Society grant RG 4925 (TEL); NIH grant R01 GM-41514 (MDC); California Institute for Regenerative Medicine (CIRM) grants RM1-01717, CL1-00502 (JFL) and TR3-05603 (JFL). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Identify mechanisms by which transplantation neural precursor cells (NPCs) improve clinical outcome through immunomodulation and promoting remyelination in different preclinical animal models of multiple sclerosis.

• Continue to define mechanisms by which allogeneic NPCs are recognized as foreign; explore whether components of the innate and/or adaptive immune response participate in rejection.

• Employ different preclinical models to confirm whether rejection of allogeneic NPCs affects clinical improvement.

• Define the therapeutic benefit of iPSC-derived NPCs in affecting disease progression and remyelination.

• Continue to interrogate the most effective route of NPC delivery, that is, intravenous, intrathecal or intraspinal injection.

• Identify soluble factor(s) secreted by NPCs that influence both immune responses and glial biology, for example, oligodendrocyte precursor cells maturation.

Notes